Minuscule molecules pack a powerful punch in immune defence

Scientists have shown that a tiny microRNA molecule called miR-155, plays a critical role in immune defence and may be a lynchpin in the immune system. The findings reported today in Science reveal that mice lacking the bic/miR-155 gene, one of the world’s first microRNA ‘knockout’ mice, have compromised immune systems and are less able to resist infection and mount an immune response to bacteria like Salmonella typhimurium, a leading cause of human gastroenteritis. They also develop symptoms similar to those of human autoimmune disorders.

The researchers from the Wellcome Trust Sanger Institute, The Babraham Institute, The Gurdon Institute and University of Cambridge, suggest that the corresponding human gene will have a similar role. This discovery provides insights into what makes our immune systems tick, what underpins diseases of the immune system like lymphoma development or autoimmunity, and how these minuscule molecules may be harnessed as effective therapeutic agents.

MicroRNAs, also known as short interfering (si) RNAs, are copied from DNA but do not contain code for protein. Rather they control gene activity by binding to specific related sequences, thereby interfering with a gene’s ability to produce the proteins that co-ordinate cellular activities.

Previous research showed that miR-155 was active in cells of the immune system and over-activity of miR-155 has been reported in B-cell lymphomas and solid tumours, implicating this region of the genome in cancer. The research team, led by the Wellcome Trust Sanger Institute, targeted the Bic/microRNA-155 gene in embryonic stem cells, which they used to transfer the mutation into mice.

“Very little is known about the function of the hundreds of microRNA genes,” said Dr Antony Rodriguez, lead author on the paper from the Wellcome Trust Sanger Institute. “Although plentiful, this class of gene had never before been knocked out in mice, the best model for human disease. But we simply did not know whether microRNA knockouts would have an effect in mice: previous knockout studies in nematode worms suggested that most microRNAs were not essential. Our findings were dramatically different.”

The effects of the miR-155 knockout swept across the immune system; although knockout of miR-155 did not appear to affect normal growth and development of cells in the immune system, three critical components that normally orchestrate the immune response, T-cells, B-cells and dendritic cells, performed less well. The ability of T-cells to produce chemical signals called cytokines, regulators of the immune response, was disrupted. Antibody production by B cells was dramatically reduced and dendritic cells, which normally ‘present’ foreign proteins to the immune system to activate a response in T-cells, were unable to do so.

“These findings demonstrate the importance of this level of control in the immune system and will lead immunologists to rethink how the immune system works,” said Dr Martin Turner, Head of the Laboratory of Lymphocyte Signalling and Development at the Babraham Institute.

To uncover how miR-155 might cause such widespread disruption, the team used microarray analysis to spot the genes whose activity was altered in the immune cells of the knockouts. The activity of over 150 genes with a large range of biological functions was reduced by miR-155, of particular note the gene c-Maf, which normally increases cytokine production and is critical for T-cell function. The team showed that miR-155 interacted directly with c-Maf, reducing its activity with consequences for activation of other genes, production of an effective immune response and susceptibility to autoimmunity and infection.

The knockout mice also develop changes to lung tissue, with scarring that is similar to some human systemic autoimmune disorders. The human Bic/miRNA-155 gene, which is 96% identical with the mature mouse microRNA, is located in a region of chromosome 21 associated with asthma, pollen sensitivity and atopic dermatitis. Hence it is thought that the equivalent human microRNA may be linked with the onset of some immune diseases.

“This dramatic finding reflects a large amount of work by collaborating groups,” said Professor Allan Bradley, Director of the Wellcome Trust Sanger Institute. “Showing that knocking out a microRNA has such dramatic effects opens new doors to understanding this novel class of gene regulation, with consequences for human health and disease. Our work builds upon the sequences of the human and mouse genomes, the power of computer analysis and microarray work and exemplifies why whole-organism research can bring understanding that cannot be developed in any other way.”

The study emphasises the value of the ES cell based knockout technology, currently being pursued on a large scale through the KOMP and EUCOMM programmes at the Wellcome Trust Sanger Institute. This success illustrates the power of the mouse to reveal function and indicates a wider role for microRNAs in animals with large genomes.

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